P1018: UPDATED RESULTS FROM MANIFEST ARM 2: EFFICACY AND SAFETY OF PELABRESIB (CPI-0610) AS ADD-ON TO RUXOLITINIB IN MYELOFIBROSIS
Authors: Marina Kremyanskaya, Claire Harrison, Prithviraj Bose, Vikas Gupta, Raajit K Rampal, Jonathan Lambert, Moshe Talpaz, Alessandro Vannucchi, Andrew Kuykendall, Jean-Jacques Kiladjian, Srdan Verstovsek, Ruben Mesa, Gozde Colak, Sandra Klein, Carmelita Alvero, John Mascarenhas
Journal: HemaSphere (2023)

Topic: 16. Myeloproliferative neoplasms - Clinical Background: Myelofibrosis (MF) is characterized by bone marrow (BM) fibrosis, splenomegaly and cytopenias. Progressive BM fibrosis results from aberrant megakaryopoiesis and proinflammatory cytokine expression, processes that are regulated by BET protein-mediated expression of genes. The current standard of care for MF is treatment with Janus kinase inhibitors (JAKis) such as ruxolitinib (RUX). However, unmet need persists due to the limited depth and durability of responses with JAKi monotherapy, high rates of discontinuation and toxicities (Tefferi A. Am J Hematol 2021;96(1):145–162). Pelabresib (CPI-0610; PELA) is an oral, small-molecule, investigational BET inhibitor that downregulates NF-κB signaling and other genes involved in MF disease pathways. PELA is under investigation as monotherapy and in combination with RUX in pts with MF in the ongoing, open-label Phase 2 MANIFEST study (NCT02158858). Aims: To present updated results from Arm 2 of the MANIFEST study on the efficacy and safety of PELA as 'add-on' to ongoing RUX in pts with suboptimal/lost response to RUX. Methods: Pts received oral PELA 125 mg QD in 21-day cycles combined with continuous oral RUX (at dose taken at time of screening). Pts in Arm 2 are stratified as transfusion dependent (TD) and nontransfusion dependent (non-TD). The primary endpoints are conversion from TD to transfusion independence (TI) in the TD cohort and ≥35% reduction in spleen volume from baseline (BL; SVR35) at Wk 24 in the non-TD cohort. Secondary endpoints include ≥50% total symptom score reduction from BL (TSS50) per MF Symptom Assessment Form v4.0 at Wk 24. Durability of responses, Hb changes, BM biopsies and safety were evaluated. Results: At data cutoff (29 July 2022), 87 pts (TD cohort = 58; non-TD cohort = 29) received PELA as add-on to RUX. Mean (SD) age was 68 (9) years; 8%, 63% and 29% pts were DIPSS Int-1, Int-2 or high risk, respectively. Pts who did not reach Wk 24 were counted as nonresponders for SVR35 and TSS50. Median treatment duration for PELA was 13.0 (range 0.25–65.4) mths. At Wk 24, 17% (15/86) of evaluable pts had SVR35 (Figure). SVR35 at any time was reported in 31% (27/86) of pts. At Wk 24, 26% (22/86) of pts had ≥25% reduction in spleen volume from BL. A total of 21% (18/86) and 19% (16/86) of pts had SVR35 response at Wk 48 and 60, respectively. Median spleen volume reduction was –17% at Wk 24. Durable (up to Wk 60) spleen volume reductions were observed (Figure). TD to TI conversion rate was 36.8% (14/38). Median TI duration was 37 wks (range 15–192). In the non-TD cohort, 24% (7/29) of pts had a Hb response (mean Hb increase of ≥1.5 g/dL from baseline without transfusions over 12 wks). TSS50 at Wk 24 was 38% (32/85) overall. A total of 55% (47/85) of pts had TSS50 at any time. Median TSS reduction was 48% at Wk 24. BM fibrosis improvement by ≥1 grade was observed in 26% of pts after 24 wks by central pathology review; 54% of pts maintained the improvement at the next available assessment or longer and 35% had ≥1 grade improvement at any time (best response). The two most common hematologic TEAEs of any grade were thrombocytopenia in 54% (Grade ≥3: 33%), and anemia in 30% (Grade ≥3: 23%) pts. A total of 26 pts (30%) reported TEAEs that led to PELA discontinuation. Serious AEs in ≥3 pts were anemia (7 pts) and pneumonia (6 pts). Conclusion: Treatment with PELA as add-on to RUX in pts with a suboptimal/lost response to RUX monotherapy resulted in durable and deepening splenic and symptom responses, and was generally well tolerated. Transfusion independence was achieved in 36.8% of pts, and improvement in BM fibrosis, as a marker of disease modification, was observed in 35% of pts.Keywords: Myeloproliferative disorder, Inhibitor, Myelofibrosis